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Updated: Sep 21, 2025
Application of AlDeSense to Stratify Ovarian Cancer Cells Based on Aldehyde Dehydrogenase 1A1 Activity
Published on: March 31, 2023
A prodrug strategy for the in vivo imaging of aldehyde dehydrogenase activity
Raul Pereira1, Renée L Flaherty1, Richard S Edwards1
1School of Biomedical Engineering and Imaging Sciences, King's College London, St. Thomas' Hospital London SE1 7EH UK tim.witney@kcl.ac.uk +44 (0)20 7188 7188, ext. 883496.
Abstract:
Therapy resistance is one of the biggest challenges facing clinical oncology. Despite a revolution in new anti-cancer drugs targeting multiple components of the tumour microenvironment, acquired or innate resistance frequently blunts the efficacy of these treatments. Non-invasive identification of drug-resistant tumours will enable modification of the patient treatment pathway through the selection of appropriate second-line treatments. Here, we have designed a prodrug radiotracer for the non-invasive imaging of aldehyde dehydrogenase 1A1 (ALDH1A1) activity. Elevated ALDH1A1 activity is a marker of drug-resistant cancer cells, modelled here with matched cisplatin-sensitive and -resistant human SKOV3 ovarian cancer cells. The aromatic aldehyde of our prodrug radiotracer was intracellularly liberated by esterase cleavage of the geminal diacetate and specifically trapped by ALDH through its conversion to the charged carboxylic acid. Through this mechanism of action, ALDH-specific retention of our prodrug radiotracer in the drug-resistant tumour cells was twice as high as the drug-sensitive cells. Acylal masking of the aldehyde afforded a modest protection from oxidation in the blood, which was substantially improved in carrier-added experiments. In vivo positron emission tomography imaging of tumour-bearing mice produced high tumour-to-background images and radiotracer uptake in high ALDH-expressing organs but was unable to differentiate between drug-sensitive and drug-resistant tumours. Alternative strategies to protect the labile aldehyde are currently under investigation.
Insights
Researchers developed a novel radiotracer to image aldehyde dehydrogenase 1A1 (ALDH1A1) activity, a marker for drug-resistant cancers. While showing promise, it could not yet distinguish between sensitive and resistant tumors in vivo.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Therapy resistance is a major challenge in cancer treatment, often limiting drug efficacy.
- Non-invasive methods to identify drug-resistant tumors are crucial for optimizing patient treatment pathways.
- Aldehyde dehydrogenase 1A1 (ALDH1A1) activity is an emerging biomarker for cancer drug resistance.
Purpose of the Study:
- To design and evaluate a novel prodrug radiotracer for non-invasive imaging of ALDH1A1 activity.
- To assess the potential of this radiotracer in differentiating between cisplatin-sensitive and cisplatin-resistant ovarian cancer cells.
Main Methods:
- Synthesis of a prodrug radiotracer designed for ALDH1A1-specific trapping.
- In vitro studies using cisplatin-sensitive and -resistant human SKOV3 ovarian cancer cells.
- In vivo positron emission tomography (PET) imaging in tumor-bearing mice.
Main Results:
- The prodrug radiotracer was effectively cleaved intracellularly, leading to ALDH-specific retention.
- ALDH-specific retention of the radiotracer was approximately twofold higher in drug-resistant cells compared to sensitive cells.
- In vivo PET imaging demonstrated high tumor-to-background ratios but failed to differentiate between sensitive and resistant tumors.
Conclusions:
- The developed prodrug radiotracer shows potential for imaging ALDH1A1 activity, a marker of drug resistance.
- Further optimization is needed to improve the stability of the radiotracer in vivo and enable differentiation between drug-sensitive and drug-resistant tumors.
